Heterogeneous Genomic Molecular Clocks in Primates

Abstract

Using data from primates, we show that molecular clocks in sites that have been part of a CpG dinucleotide in recent past (CpG sites) and non-CpG sites are of markedly different nature, reflecting differences in their molecular origins. Notably, single nucleotide substitutions at non-CpG sites show clear generation-time dependency, indicating that most of these substitutions occur by errors during DNA replication. On the other hand, substitutions at CpG sites occur relatively constantly over time, as expected from their primary origin due to methylation. Therefore, molecular clocks are heterogeneous even within a genome. Furthermore, we propose that varying frequencies of CpG dinucleotides in different genomic regions may have contributed significantly to conflicting earlier results on rate constancy of mammalian molecular clock. Our conclusion that different regions of genomes follow different molecular clocks should be considered when inferring divergence times using molecular data and in phylogenetic analysis. The rate at which mutations accumulate in a genome, referred as a “molecular clock,” is an instrumental tool in molecular evolution and phylogenetics. Different types of mutations occur via distinctive molecular pathways. In particular, while most mutations occur from errors in DNA replication, spontaneous deamination of methylated CpG dinucleotides is another important source of mutation in mammalian genomes. Molecular clock studies typically combined all types of mutations together. In this paper, the authors analyze molecular clocks of replication-origin and methylation-origin mutations separately. By utilizing high-quality sequence data from several primate species and fossil calibration, the authors demonstrate that the two types of mutations follow statistically different molecular clocks. Methylation-origin mutations accumulate relatively constantly over time, while replication-origin mutations scale with generation-times. Therefore, the genomic molecular clock, as a whole, is shaped by the molecular origins of mutations that have accumulated over time. The authors' results have direct implications on phylogenetic analyses, estimation of species divergence dates, and studies of the mechanisms and processes of evolution, where molecular clocks are imperative.